Aqueous based pharmaceutical formulations of water-soluble prodrugs of propofol

ABSTRACT

The present invention is directed to aqueous based formulations of water-soluble prodrugs of propofol. The formulations comprise in aqueous medium an effective amount of the water-soluble prodrug of propofol and an effective amount of an antioxidant. In one embodiment, the formulation also contains a tonicity modifier. The formulations are particularly useful as intravenous injections. The formulations preferably are buffered to a pH suitable for minimizing degradation of the prodrug during storage. Advantageously, the formulations can be prepared without the use of harmful co-solvents or surfactants, and are stable at room temperature over extended periods of time.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims benefit under 35 U.S.C. § 119(e) to U.S.provisional application 60/342,755, filed Dec. 28, 2001, the disclosureof which is incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to aqueous based formulations ofwater-soluble prodrugs of propofol.

BACKGROUND OF THE INVENTION

The successful delivery of a pharmaceutical to a patient is of criticalimportance in the treatment of disorders. However, the use of manyclinical drugs with known bioactive properties is limited by the drugs'very low water solubility. As a result of low water solubility, manydrugs often are formulated in co-solvent pharmaceutical vehicles,including surfactants. Such surfactants have been shown to lead tosevere side effects in humans that limit the clinical safety of thesedrugs and therefore the treatment of several disorders.

Propofol (2,6-diisopropylphenol or DIP) is a low molecular weight phenolderivative that is widely used as a hypnotic or sedative agent forintravenous administration in the induction and maintenance ofanesthesia or sedation in humans and animals. Among its usefulcharacteristics as an anesthetic drug are: administration via theintravenous route, rapid onset and offset of anesthesia, rapidclearance, and a side-effect profile that makes it preferable to otherinjectable anesthetics, such as barbiturates.

The use of injectable anesthetic agents generally, and of propofolspecifically, in the induction and maintenance of general anesthesia hasgained widespread acceptance in anesthetic care over the last 15 years.Intravenous anesthesia with propofol has been described to have severaladvantages over preexisting methods, such as more readily toleratedinduction, since patients need have no fear of masks, suffocation, orthe overpowering smell of volatile anesthetics; rapid and predictablerecovery; readily adjustable depth of anesthesia by adjusting the IVdose of propofol; a lower incidence of adverse reactions as compared toinhalation anesthetics; and decreased dysphoria, nausea, and vomitingupon recovery from anesthesia (Padfield N. L., Introduction, History andDevelopment, in: Padfield N L (Ed.) Ed., Total Intravenous Anesthesia,Butterworth Heinemann, Oxford 2000).

In addition to its sedative and anesthetic effects, propofol has a rangeof other biological and medical applications. For example, it has beenreported to be an anti-emetic (McCollum J S C et al., Anesthesia 43(1988) 239), an anti-epileptic (Chilvers C. R., Laurie P. S., Anesthesia45 (1990) 995), and an anti-pruritic (Borgeat et al., Anesthesiology 76(1992) 510). Anti-emetic and anti-pruritic effects are typicallyobserved at sub-hypnotic doses, i.e. at doses that achieve propofolplasma concentrations lower than those required for sedation oranesthesia. Anti-epileptic activity, on the other hand, is observed overa wider range of plasma concentrations (Borgeat et al., Anesthesiology80 (1994) 642). It has further been speculated that propofol, due to itsantioxidant properties in biological systems, may be useful in thetreatment of inflammatory conditions, especially inflammatory conditionswith a respiratory component, and in the treatment of neuronal damagerelated to neurodegeneration or trauma. Such conditions are believed tobe associated with the generation of reactive oxygen species andtherefore amenable to treatment with antioxidants (see, e.g. U.S. Pat.No. 6,254,853 to Hendler et al.)

Propofol typically is formulated for clinical use as a oil-in-wateremulsion. The formulation has a limited shelf-life and has been shown tobe sensitive to bacterial or fungal contamination, which has led toinstances of post-surgical infections (Bennett S. N. et al., N Eng. JMed 333 (1995) 147). Due to the dense, white color of the formulation,bacterial or fungal contamination cannot be detected by visualinspection of the vial in the first instance.

Not only is propofol poorly water soluble, but it also causes pain atthe injection site, which must often be alleviated by using a localanesthetic (Dolin S. J., Drugs and Pharmacology, in: N. Padfield, Ed.,Total Intravenous Anesthesia, Butterworth Heinemann, Oxford 2000). Dueto its formulation in a lipid emulsion, its intravenous administrationis also associated with undesirable hypertriglyceridemia in patients,especially in patients receiving prolonged infusions (Fulton B. andSorkin E. M., Drugs 50 (1995) 636). Its formulation as a lipid emulsionfurther makes it difficult to co-administer other IV drugs. Any physicalchanges to the formulation, such as a change in lipid droplet size, canlead to changes in the pharmacological properties of the drug and causeside effects, such as lung embolisms.

It has further been reported that the use of propofol in anesthesiainduction is associated with a significant incidence of apnea, whichappears to be dependent on dose, rate of injection, and pre-medication(Reves, J. G., Glass, P. S. A., Lubarsky D. A., Non-barbiturateIntravenous Anesthetics. In: R. D. Miller et al., Eds, Anesthesia.5^(th) Ed. Churchill Livingstone, Philadelphia, 2000). Respiratoryconsequences of administering anesthetic induction doses of propofol,including a reduction in tidal volume and apnea, occur in up to 83% ofpatients (Bryson et al., Drugs 50 (1995) at 520). Induction doses ofpropofol are also known to have a marked hypotensive effect, which isdose- and plasma concentration-dependent (Reves et al., supra). Thehypotension associated with peak plasma levels after rapid bolusinjection of propofol sometimes requires the use of controlled infusionpumps or the breaking-up of the induction bolus dose into severalsmaller incremental doses. Further, the short duration ofunconsciousness caused by bolus induction doses renders propofolsuitable for only brief medical procedures. For all the above reasons,propofol for induction and/or maintenance of anesthesia must normally beadministered in an in-patient setting under the supervision of ananesthesiologist, and is often considered inappropriate for use bynon-anesthesiologists in an ambulatory or day case setting.

In addition to its use in induction and maintenance of anesthesia,propofol has been used successfully as a sedative to accompany eitherlocal or regional anesthesia in conscious patients. Its sedativeproperties have also been exploited in diagnostic procedures that havean unsettling effect on conscious patients, such as colonoscopy orimaging procedures. Propofol has also been used as a sedative inchildren undergoing diagnostic imaging procedures or radiotherapy. Arecent development is that of patient-controlled sedation with propofol.This technique is preferred by patients and is as effective asanesthesiologist-administered sedation.

Compared with the widely used sedative midazolam or other such agents,propofol provided similar or better sedative effects when the quality ofsedation and/or the amount of time that patients were at adequate levelsof sedation were measured (see Fulton B. and Sorkin E. M., Drugs 50(1995) 636). The faster recovery and similar or less amnesia associatedwith propofol makes it an attractive alternative to other sedatives,particularly for patients requiring only short sedation. However,because of the potential for hyperlipidemia associated with the currentpropofol formulation, and the development of tolerance to its sedativeeffects, the usefulness of propofol for patients requiring longersedation is less well established. For all the reasons given above,there exists a clinical need for aqueous, stable formulations of safe,injectable, or infusible sedative or hypnotic agents.

The development of water soluble and stable prodrugs of propofol, whichis described in U.S. Pat. No. 6,204,257 to Stella et al., has made itpossible to address these heretofore unmet needs, and to explore thepharmaceutical advantages of an aqueous propofol-prodrug in theinduction and maintenance of sedation and anesthesia in patients. Theprodrugs of the present invention differ from propofol in that the1-hydroxy-group of propofol is replaced with a phosphonooxymethyl ethergroup:

While not wanting to be bound by theory, the prodrug is believed toundergo hydrolysis by endothelial cell surface alkaline phosphatases torelease propofol.

Propofol currently is formulated as an oil-in-water emulsion. Forexample, U.S. Pat. No. 6,177,477 to George et al. describes a sterilepharmaceutical composition of propofol for parenteral administrationcomprising an oil-in-water emulsion in which propofol is dissolved in awater-immiscible solvent and is emulsified with water containingtromethamine as a preservative. The preservative is said to be presentin an amount sufficient to prevent any significant growth ofmicroorganism for at least 24 hours in the event of extrinsiccontamination. Because propofol is formulated as an emulsion, it isdifficult and questionable to add other drugs to the formulation, asphysical changes to the formulation, such as an increase in oil dropletsize, can lead to lung embolisms or other complications.

It would be desirable to develop a room temperature-stable,aqueous-based formulation for water-soluble prodrugs of propofol,especially a formulation that does not require potentially toxicco-solvents or the use of surfactant.

BRIEF SUMMARY OF TE INVENTION

The present invention is directed to aqueous-based pharmaceuticalformulations of water-soluble prodrugs of propofol. The pharmaceuticalformulation comprises in an aqueous medium a therapeutically effectiveamount of a compound represented by Formula I:

wherein each Z is independently selected from the group consisting ofhydrogen, alkali metal ion, and amine, and an effective amount of anantioxidant. The pharmaceutical formulation may also contain othercomponents, such as a tonicity modifier and/or a buffer.

According to another embodiment of the present invention, anaqueous-based formulation comprises an effective amount of a compound ofFormula I, an antioxidant, and optionally a buffer. The amount of thecompound of Formula I present in the formulation is such that thetonicity, i.e., osmolality, is essentially the same as normalphysiological fluids.

Preferred formulations of the present invention are particularly usefulas intravenous injections. The formulations preferably are buffered to apH suitable for minimizing degradation of the prodrug during storage.The formulations can be prepared without the use of harmful co-solventsor surfactants, and are stable at room temperature over extended periodsof time.

DETAILED DESCRIPTION OF TH INVENTION

The pharmaceutical formulations of the present invention comprise inaqueous medium, a therapeutically effective amount of a water-solubleprodrug represented by Formula I:

wherein each Z is independently selected from the group consisting ofhydrogen, alkali metal ion, and amine, and an effective amount of anantioxidant. The aqueous-based formulations may also contain othercomponents, such as a tonicity modifier and/or a buffer.

Methods for synthesizing the derivatives of Formula I are described inU.S. Pat. No. 6,204,257 B1, the disclosure of which hereby isincorporated by reference in its entirety. A representative example of acompound of Formula I is O-phosphonooxymethyl-propofol, the structure ofwhich is illustrated below:

The relative amount of the prodrug in the formulation can vary over awide range depending on a variety of factors including but not limitedto the identity of the prodrug, the bioactivity of the parent drug for aparticular disorder being treated, and the intended mode ofadministration. The relative amount of the prodrug in the formulationmost often ranges from about 0.5 to about 20% (w/v), more usually fromabout 1 to about 10%.

Any pharmaceutically acceptable aqueous medium, such as water ofsufficiently high purity, may be used in the formulations of the presentinvention.

The antioxidant prevents or reduces oxidative degradation of the prodruginto poorly water-soluble compounds. The prodrug is believed to beconverted to DIP by aqueous hydrolysis or by enzymatic processes in theblood. DIP in turn is converted to the related substances quinone andhydroquinone by an oxidative process. All three of DIP, quinone, andhydroquinone are poorly water-soluble. It is desirable to minimize theformation or presence of poorly water-soluble compounds in theaqueous-based formulation because even at low concentrations, thesecompounds impart a yellow color to the solution. Over time, the solutionbecomes hazy, and eventually particles form.

The antioxidant should be present in at least a minimum amount thatprovides some reduction in oxidative degradation of the water-solubleprodrug. There is no particular maximum concentration contemplated. Theconcentration of the antioxidant in the aqueous formulation most oftenranges from about 0.1 to about 1% (w/v). During manufacturing, thesolution may be sparged with nitrogen to reduce the level of dissolvedoxygen present in the formulation, which also provides protectionagainst oxidative degradation.

A variety of antioxidants may be used in the formulations of the presentinvention. The particular antioxidant used can be suitably selected inaccordance with such factors as the particular prodrug(s) present in theformulation. Non-limiting examples of antioxidants includemonothioglycerol, glutathione, citric acid, ascorbic acid, sodiummetabisulfite, and sodium sulfite. EDTA, a metal chelator, providesprotection from catalytic oxidation of phenols.

Because preferred formulations are intended for parenteraladministration, it is preferable to make up solutions such that thetonicity, i.e., osmolality, is essentially the same as normalphysiological fluids in order to prevent post-administration swelling orrapid absorption of the composition because of differential ionconcentrations between the composition and physiological fluids. Ifneeded, a tonicity modifier is present in a suitable amount that can beascertained by persons skilled in the art with the aid of no more thanroutine experimentation. When used, the amount of tonicity modifier usedmost often ranges from about 0.1 to about 1% (w/v). The particulartonicity modifier used is not critical to the practice of the presentinvention. Non-limiting examples of suitable tonicity modifiers includesodium chloride, glycerin, boric acid, calcium chloride, dextrose, andpotassium chloride.

The pH of the formulation preferably is maintained to provide long-termstability of the formulation at room temperature. In most cases asuitable pH is from about 7 to about 10, and preferably is at leastabout 8.5. The solution may be buffered using any standard buffereffective in the pH range of 7-10, e.g., carbonate, phosphate, borate,or glycine. One preferred buffer is tromethamine(2-amino-2-hydroxymethyl-1,3-propanediol), also commonly referred to asTRIS. The amount of buffer needed for this purpose most often rangesfrom about 10 to about 25 mmol.

Other components may be present in the formulation. For example, in thecase of a multi-dose vial, a preservative may be included, such asbenzyl alcohol. The formulation also may contain co-solvents such aspolyethylene glycol (PEG 200, PEG 400), propylene glycol, and/orethanol. Concentrations of the co-solvents can vary over a wide range,most often from 0 to about 20%.

The formulations of the present invention may be administered via anysuitable route of administration. Formulations for intravenous injectionmay be packaged, for example, in a glass vial, in a pre-filled syringe,or in an ampoule. The formulations may be administered with standard IVdiluent solutions, e.g., D5W, normal saline, or Lactated Ringer'ssolution.

Suitable dosages can be ascertained depending on such factors as theidentity of the prodrug and the type of the disorder being treated.Dosages may be, for example, in the range of about 0.1 to about 100mg/kg of body weight, or about 5 to 500 mg/ml. As will be apparent topersons skilled in the art, many factors that modify the action of thedrug will be taken into account in determining the dosage including theage, sex, diet and physical conditions of the patient.

For administering the propofol prodrug, an anesthesiologist skilled inthe art of anesthesia will be able to ascertain, without undueexperimentation, an appropriate treatment protocol for administering aformulation of the present invention. The dosage, mode and schedule ofadministration are not particularly restricted, and will vary with theparticular indication. The formulation may be administered parenterally.The dosage may be, for example, in the range of 0.5 to 10 mg/kgadministered according to procedures for induction of general anesthesiaor maintenance of general anesthesia. Alternatively, the formulation maybe administered by parenteral infusion, the dosage may be, for example,in the range of 2 μg/kg/min to 800 μg/kg/min administered according toprocedures for maintenance of general anesthesia, initiation andmaintenance of MAC sedation or initiation and maintenance of ICUsedation.

EXAMPLES

The following examples are provided to illustrate the present inventionand should not be construed to limit the scope of the present inventionas described elsewhere herein.

Example 1

This example illustrates preparing a 2% solution of O-phosphonooxymethylpropofol, a water-soluble prodrug of propofol. The aqueous-basedformulation has the composition set forth in Table 1 below. TABLE 1Component Concentration O-phosphonooxymethyl propofol 2% (20 mg/ml)Sodium Chloride 0.4% Monothioglycerol 0.5% TRIS, USP (Tromethamine) 20mmol pH 9 ± 0.5

Sodium chloride (28 g) was added to 7 l of water and stirred untildissolved. Next, TRIS (2-amino-2-hydroxymethyl-1,3-propanediol) (20mmol) was added with stirring. The solution was then sparged withnitrogen gas. Monothioglycerol (35 g) then was added with stirring.O-phosphonooxymethyl propofol (140 g) was added, and the solution wasstirred until it dissolved. The solution was filtered and poured intovials.

Example 2

This example illustrates preparing a 4% solution of O-phosphonooxymethylpropofol. The aqueous-based formulation has the composition set forth inTable 2 below. TABLE 2 Component Concentration O-phosphonooxymethylpropofol 4% (40 mg/ml) Monothioglycerol 0.25% TRIS, USP (Tromethamine)20 mmol pH 9 ± 0.5

TRIS (20 mmol) was added to 7 l of water with stirring. The solution wasthen sparged with nitrogen gas. Monothioglycerol (17.5 g) then was addedwith stirring. O-phosphonooxymethyl propofol (280 g) was added, and thesolution was stirred until it dissolved. The solution was filtered andpoured into vials.

Example 3

This example illustrates preparing a 2% solution of O-phosphonooxymethylpropofol having the composition set forth in Table 3 below. TABLE 3Component Concentration O-phosphonooxymethyl propofol 2% (20 mg/ml)Sodium Chloride 0.4% Monothioglycerol 0.5% Carbonate buffer 20 mmol pH 9± 0.5

Sodium chloride (28 g) is added to 7 l of water and stirred untildissolved. Next, carbonate buffer (20 mmol) was added with stirring. Thesolution was then sparged with nitrogen gas. Monothioglycerol (35 g)then was added with stirring. O-phosphonooxymethyl propofol (140 g) wasadded, and the solution was stirred until it dissolved. The solution wasfiltered and poured into vials.

Example 4

This example illustrates preparing an unbuffered 2% solution ofO-phosphonooxymethyl propofol having the composition set forth in Table4 below. TABLE 4 Component Concentration O-phosphonooxymethyl propofol2% (20 mg/ml) Sodium Chloride 0.4% Monothioglycerol 0.5% pH 9 ± 0.5

Sodium chloride (28 g) was added to 7 l of water and stirred untildissolved. The solution is then sparged with nitrogen gas.Monothioglycerol (35 g) then was added with stirring.O-phosphonooxymethyl propofol (140 g) was added, and the solution wasstirred until it dissolved. The solution was filtered and poured intovials.

Example 5

This example illustrates that a 2% solution of O-phosphonooxymethylpropofol can be prepared using 0.1% sodium sulfite as an antioxidant.The aqueous-based formulation has the composition set forth in Table 5below. TABLE 5 Component Concentration O-phosphonooxymethyl propofol 2%(20 mg/ml) Sodium Chloride 0.4% Sodium Sulfite 0.1% TRIS, USP(Tromethamine) 20 mmol pH 9 ± 0.5

Sodium chloride (28 g) is added to 7 l of water and is stirred until itdissolves. Next, TRIS (2-amino-2-hydroxymethyl-1,3-propanediol) (20mmol) is added with stirring. The solution is then sparged with nitrogengas. Sodium sulfite (7 g) then is added with stirring.O-phosphonooxymethyl propofol (140 g) is added, and the solution isstirred until it dissolves. The solution is filtered and poured intovials.

While particular embodiments of the present invention have beendescribed and illustrated, it should be understood that the invention isnot limited thereto since modifications may be made by persons skilledin the art. The present application contemplates any and allmodifications that fall within the spirit and scope of the underlyinginvention as disclosed and claimed herein.

1. A pharmaceutical formulation comprising in an aqueous medium: (i) atherapeutically effective amount of a compound represented by theformula

wherein each Z is independently selected from the group consisting ofhydrogen, alkali metal ion, and amine; and (ii) an effective amount ofan antioxidant.
 2. The formulation of claim 1 wherein the antioxidant isselected from the group consisting of monothioglycerol, glutathione,citric acid, ascorbic acid, sodium metabisulfite, sodium sulfite, andEDTA.
 3. The formulation of claim 2 wherein the concentration of theantioxidant is from about 0.1 to about 1% (w/v).
 4. The formulation ofclaim 1 further comprising a tonicity modifier.
 5. The formulation ofclaim 4 wherein the tonicity modifier is selected from the groupconsisting of sodium chloride, glycerin, boric acid, calcium chloride,dextrose, and potassium chloride.
 6. The formulation of claim 5 whereinthe concentration of the tonicity modifier is from about 0.1 to about 1%(w/v).
 7. The formulation of claim 1 further comprising a buffer.
 8. Theformulation of claim 7 wherein the buffer is2-amino-2-hydroxymethyl-1,3-propanediol.
 9. A pharmaceutical formulationcomprising in an aqueous medium: (i) a therapeutically effective amountof O-phosphonooxymethyl propofol; (ii) from about 0.1 to about 1% (w/v)of an antioxidant selected from the group consisting ofmonothioglycerol, glutathione, citric acid, ascorbic acid, sodiummetabisulfite, sodium sulfite, and EDTA; and (iii) from about 0.1 toabout 1% (w/v) of a tonicity modifier selected from the group consistingof sodium chloride, glycerin, boric acid, calcium chloride, dextrose,and potassium chloride.